Method and system for colloid exchange therapy

ABSTRACT

The present invention relates to a method and system for using a hemofilter to treat IMRD, hepatic failure, exogenous intoxication and other conditions associated with toxins in a patient&#39;s blood. One treatment includes the use of a very large pore hemofilter to remove target complex molecules and/or target molecules from a patient&#39;s blood and to infuse a replacement fluid into the patient&#39;s blood to maintain a prescribed albumin concentration in the patient&#39;s blood.

RELATED APPLICATIONS

[0001] This application claims the benefit of previously filedprovisional application Serial No. 60/204,398, filed on May 16, 2000 andprovisional patent application Serial No. 60/230,106, filed on Sep. 5,2000, both provisional applications having the title of METHOD ANDSYSTEM FOR COLLOID EXCHANGE THERAPY.

TECHNICAL FIELD

[0002] The present invention relates generally to systems, methods, anddevices used for hemofiltration. More specifically, the presentinvention relates to very large pore hemofiltration (“VLPH”) fortreating liver failure, for treating exogenous toxin exposures, and fortreating inflammatory mediator-related diseases (“IMRD”) includingsepsis and septic shock, which include systemic inflammatory responsesyndrome (“SIRS”), multiorgan system dysfunction syndrome (“MODS”),multiorgan system failure (“MOSF”),and compensatory anti-inflammatoryresponse syndrome (“CARS”), and for treating other conditions associatedwith toxin circulating in a patient's blood.

BACKGROUND OF THE INVENTION

[0003] Discussed herein are three subjects. First, devices andprocedures for the therapeutic manipulation of target receptormolecules, target complex molecules, and target molecules in immunemediator related disease, and hepatic failure, and exogenousintoxication. Second, selected physiologic roles of albumin in health,immune mediator related disease, hepatic failure and exogenousintoxication, in particular effects of oncotic pressure and binding ofphysiologic or pathologic molecules. Third, the physiologic roles ofsoluble receptor and carrier molecules with respect to pro- andanti-inflammatory mediators (“IM”) in particular and toxins in general.

[0004] Medical Blood Filtration

[0005] Treatment of certain diseases by filtration of blood is wellestablished medical practice. Dialysis, using dialysis filters, whichremove molecules with molecular weights up to 5,000 to 10,000 Dalton, isused to treat chronic and some acute renal failure. Conventionalhemofiltration, discussed below, is used to treat acute renal failure,and in some cases, chronic renal failure. Plasmapheresis, using plasmafilters or centrifuge techniques which remove molecules with molecularweights of 1,000,000 to 5,000,000 Dalton or more, is used to treatdiseases associated with high molecular weight pathologicimmunoglobulins or immune complexes, (e.g., multiple myeloma, lupusvasculitis, etc.).

[0006] Conventional hemofilters are well known medical devices commonlyused to filter the blood of a patient with acute renal failure, and insome-cases, chronic renal failure. The hemofilter may be used either forconvective or dialytic depuration of blood. Many hemofilters are on themarket with various characteristics. However, conventionally they allshare one major characteristic, which is a nominal or effectivemolecular weight cutoff of less than 69,000 Dalton—the molecular weightof albumin. Conventional hemofilters are generally designed to minimizeor avoid sieving of albumin. The reason is that the removal of albuminin the application of renal failure treatment is of no benefit, andwould be a deleterious side effect, because the oncotic pressure ofplasma would be reduced and edema promoted. Albumin could be replaced,but would add cost and risk with no therapeutic benefit. Therefore,conventional hemofilters are designed to avoid sieving of albumin.

[0007] Plasmapheresis has the objective of sieving all plasma proteins,especially all classes of immunoglobulins and immune complexes. Thisrequires a molecular weight cutoff of from 1 million to 5 millionDalton, or more. Plasmapheresis membranes are designed to reject onlycellular elements of blood, and are the most extreme of the bloodfiltration techniques designed to produce an acellular filtrate.

[0008] Physiology of Albumin and Soluble Receptor and Carrier Molecules:

[0009] Serum albumin serves a number of vital functions, two of theseare its oncotic function and its chemical binding and transport of bothphysiologic and pathologic molecules. Albumin provides 80% of theoncotic pressure of plasma. This oncotic pressure keeps plasma waterwithin the blood-vascular space, preserving the plasma water componentof the blood volume, and preventing tissue edema by drawing tissue fluidback into the plasma from tissue. Albumin normally is present in humanplasma at a concentration of about 3.5 to 5.0 gm/100 ml. If albuminconcentration declines, typically to a concentration of <2.5 gm/100 ml,then oncotic pressure drops below its critical level, and edema fluidaccumulates in tissues, body cavities (e.g., ascites, pleural effusion),and in air spaces in the lung (e.g., pulmonary edema). This accumulationof edema fluid may result in vital organ dysfunction, increasedsusceptibility to infection, and hyper-coagulable states.

[0010] Thus, depletion of albumin molecules to the extent that oncoticpressure is excessively reduced is to be avoided.

[0011] The chemical binding and transport functions of albumin arenumerous. In most cases, potentially biologically active molecules inthe blood circulation only have their biologic effects when they arefree in suspension or solution in the plasma water. In this free state,the molecule is able to interact with its receptor(s) to bring aboutbiologic effects. Such biologic actions may be agonistic orantagonistic. Binding of a potentially biologically active molecule toalbumin or other carrier or soluble receptor molecule usuallyinactivates the molecule by preventing combination with its tissuereceptor. In some instances, the binding functions are part of normalphysiologic process. For example when albumin binds calcium or magnesiumions, it is a dynamic process that helps to preserve the properconcentration of ionized calcium in the plasma water. If ionized calciumdrops, calcium is released from albumin to restore normal plasma waterionized calcium. In other instances, the binding function of albumin andother receptor molecules protects against disease causing molecules byparticipating in their inactivation and detoxification.

[0012] Another major function of albumin is its role in detoxification,in which it binds endogenous or exogenous toxins. In this role, albuminacts both to detoxify the toxin by binding and therefore inactivatingit, and also as a carrier molecule, transporting the toxic molecule tothe liver for chemical transformation (detoxification) and excretion, orto the kidney for excretion. Endogenous toxins arise from a great manypathologic bodily processes. During sepsis and septic shock,inflammatory mediators (“IM”) are produced in excess. At the site oflocal tissue injury or infection, IM serve the vital immune functions ofremoval and healing of injured or dead tissue, or resisting ordestroying infecting organisms. When IM become excessive and spill overinto the general circulation, they may become toxic to the body causingthe systemic inflammatory response syndrome, with complicatingmultiorgan dysfunction syndrome and multiorgan system failure. These IMare carried in the plasma bound to albumin, bound to other receptormolecules, or free in plasma water. Binding by albumin and otherreceptor molecules moderates and ablates the effects of circulating IM.When the binding capacity is exceeded, the circulating IM become muchmore toxic and the moderating effects of albumin-carrier moleculebinding are exceeded.

[0013] Other diseases, such as rheumatoid arthritis, pemphigoidvulgaris, multiple sclerosis, lupus, graft versus host disease andsimilar conditions, are similarly caused by excess circulating IM. Theseconditions generally result from an autoimmune process in which IM,either physiologic or pathologic, are dysfunctionally produced and aretherefore toxic in any amount, or produced in dysfunctionally large andtoxic quantities. Sepsis-septic shock and the autoimmune diseases, eachresulting from dysfunctional and/or dysfunctionally abundant IM, may bereferred to in aggregate as Inflammatory Mediator Related Disease(“IMRD”).

[0014] Liver failure is a complex disorder with an intricatepathophysiology and diverse effects on many vital organs. It ischaracterized by the accumulation in the body of many toxins that arisefrom body metabolic processes, which, under normal conditions, arequickly detoxified and eliminated by the liver, but which, in liverfailure, accumulate in the body. The pathologic effects of liver failureare varied and include bleeding (failure of liver to produce clottingfactors), infection (failure of liver to remove organisms translocatedfrom the gut into the portal circulation), and the accumulation, asnoted above, of various liver failure toxic substances which have beenonly partially characterized. The lethal effect of these liver failuretoxic substances is hepatic coma with progressive cerebral edema andeventual brain stem herniation and death. Liver failure toxic substancesare extensively bound by albumin. While several supportive therapies arein use to reduce these toxic substances and ameliorate the effects ofhepatic failure, none have shown a clear or consistent benefit.

[0015] Exogenous toxin exposures such as suicide attempts, accidentaltoxin ingestions and environmental (industrial, agricultural, etc.)toxin exposures are of great diversity. The majority of these exogenoustoxins are bound to albumin and other tissues, thus excretion by naturalmeans (kidney elimination) or artificial means (dialysis) is severelylimited. Therapy for nearly all these intoxications is supportive only.In most intoxications, which are mild or moderate, simple supportivecare and allowing the body's own detoxification mechanisms time to work,is satisfactory. However, in severe intoxications, particularly withmore dangerous chemicals (e.g., tricyclic antidepressants, aspirin, etc)removal by some extracorporeal means would be desirable. However,current methods are not adequate to overcome binding of exogenous toxinsto albumin or tissue and remove them from the body.

[0016] Not all carrier molecules inhibit the function of the boundmolecule; in some cases, biologic activity of the bound molecule isenhanced by binding to a carrier molecule. For example,lipopolysaccharide (endotoxin) stimulation of cyotkine production isenhanced by low levels of lipopolysaccharide binding protein (LBP). LBPis an acute phase carrier protein made by the liver.

SUMMARY OF THE INVENTION

[0017] In accordance with teachings of the present invention, a methodand system for a new type of hemofiltration referred to as very largepore hemofiltration (“VLPH”) is provided. Very large pore hemofiltrationincludes sustained removal of albumin and similar large receptormolecules and carrier molecules for the purpose of removing both boundand unbound pathologic molecules or toxins. U.S. Pat. No. 5,571,418teaches the use of a hemofilter with a nominal molecular weight cutoffof 100 to 150 kiloDalton (1,000 Daltons=1 kiloDalton) for the treatmentof sepsis, septic shock, and other conditions. The purpose of the filterin the ′418 patent is to remove circulating IM. A 100-kiloDaltonhemofilter may initially sieve small amounts of albumin, but even if itdoes, albumin sieving quickly becomes negligible due to membranepolarization soon after the procedure begins.

[0018] Membrane polarization is well recognized in filtration process ofblood and consists of the accumulation of a protein layer or “cake”onthe membrane surface which characteristically reduces its sievingcapacity (e.g., effective molecular weight cutoff) by 30 to 50%. Theapplication of the 100 kD filter accepts the possibility of minoralbumin sieving as a side effect of its therapeutic application.Therefore, a very large pore hemofiltration membrane suitable for thetherapy of the present invention often requires a nominal molecularweight cutoff of >100 kD. Hemofilters with a nominal molecular weightcutoff ≦100 kiloDalton are generally not capable of sustained effectiveremoval of albumin, and large receptor and carrier molecules, especiallywhen target molecules are bound to them.

[0019] VLPH is distinct from plasmapheresis in the following criticalways. First, VLPH seeks sieving of proteins such as albumin, solubletumor necrosis factor receptor 75 (molecular weight =75,000 Dalton), andsimilar soluble receptor and carrier molecules for the reasons statedabove. VLPH specifically avoids removal of significant amounts ofimmunoglobulins and similar large molecules because removal of thesemolecules is associated with a marked increase in the risk ofopportunistic infection.

[0020] Inflammatory mediator related disease (“IMRD”), liver failure,exogenous intoxication, and other conditions associated with toxinscirculating in the blood are similar in that each is a severe pathologicprocess, often acutely life threatening, and in need of urgent oremergent therapy. Therefore, VLPH should generally be most effectivewhen initial high volumes of ultrafiltrate are removed (exchanged forreplacement fluid) for limited periods of time. Thus, the presentinvention will often be most effective at initial adult patientultrafiltration rates of from 2-5 liters/hour, or even up to 15 to 20liters/hour or more, and for initial treatment times ranging from about4-10 hours, but generally not more than 24 hours at a time. Conventionalhemofiltration produces ultrafiltration rates of about 1-2 liters/hourand is used on a continuous basis over a few to several days.

[0021] Devices and procedures, incorporating teachings of the presentinvention, fulfill longstanding needs for an effective therapy to treatIMRD, liver failure, exogenous toxin exposure and other conditionsassociated with toxins in the blood by removing target molecules andtarget complex molecules from a patient's blood. Such devices andprocedures may be generally described as plasma colloid exchange therapy(PCET).

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] A more complete and thorough understanding of the presentinvention and advantages thereof may be acquired by referring to thefollowing description taken in conjunction with the accompanyingdrawings, in which like reference numbers indicate like features, andwherein:

[0023]FIG. 1 is a schematic diagram showing one example of a very largepore hemofiltration system incorporating teachings of the presentinvention; and

[0024]FIG. 2 is a block diagram showing one example of a method fortreating a wide variety of conditions associated with inflammatorymediators and bound or unbound toxins in a patient's blood in accordancewith teachings of the present invention using a hemofiltration system,replacement fluid for ultrafiltrate discarded from the hemofiltrationsystem and an optional ultrafiltrate recycling device.

DETAILED DESCRIPTION OF THE INVENTION

[0025] Preferred embodiments of the invention and its advantages arebest understood by reference to FIGS. 1 and 2.

[0026] For purposes of this patent application, albumin, receptormolecules, and carrier molecules will be referred to collectively as“target receptor molecules”. A wide variety of naturally occurringreceptor molecules and carrier molecules may be satisfactorily used withthis invention. Also, receptor molecules and carrier molecules may bedesigned and artificially created to bind with specific target moleculesor general classes of target molecules. The term “clean target receptormolecule” refers to a receptor molecule or a carrier molecule which isnot contaminated with or bound with a target molecule. The term “cleanalbumin” refers to albumin which is not contaminated with or bound witha target molecule.

[0027] For purposes of this patent application, albumin with bound IMand/or toxins, receptor molecules with bound IM and/or toxin, andcarrier molecules with bound IM and/or toxin, will be referred tocollectively as “target complex molecules”. For purposes of this patentapplication, unbound IM, and unbound toxin (whether endogenous orexogenous) will be referred to collectively as “target molecules.”Endogenous toxins include but are not limited to IM, liver failurerelated toxins, and metabolites of certain exogenous toxins. Exogenoustoxins include chemicals such as medicine taken in excess, industrialand/or agricultural chemical exposures, and the like.

[0028] Various embodiments of the present invention include a process,method, and system to treat IMRD, to treat hepatic failure and coma, totreat exogenous intoxication, and/or to treat other conditionsassociated with bound and unbound toxins in a patient's blood includingtarget molecules and target complex molecules.

[0029] One example of a very large pore hemofiltration (VLPH) systemincorporating teachings of the present invention is shown in FIG. 1.System 90 may be used to treat mammals such as patient 100. System 90may include a very large pore hemofilter 102, blood lines 101, 103, 105,107 and ultrafiltrate lines 112, 127 and 121, source 150 of replacementfluid and optional ultrafiltrate recycling device 170. System 90represents only one example of an extracorporeal blood circuit which maybe used to treat patients in accordance with teachings of the presentinvention. For example, ultrafiltrate recycling device 170 may not beincluded in some systems used to treat a patient using hemofilter 102.For other systems, ultrafiltrate may flow directly from hemofilter 102to waste reservoir 119.

[0030] Very large pore hemofilter 102 receives a stream of blood frompatient or mammal 100 and removes ultrafiltrate from the stream of bloodand thereby creates a stream of filtered blood and a stream ofultrafiltrate flowing through tubing 112. The filtered blood ispreferably returned to patient 100. All or portions of the ultrafiltratemay be discarded to waste reservoir 119. Alternatively, all or portionsof the ultrafiltrate may be cleaned and returned to patient 100.

[0031] Very large pore hemofilter 102 preferably sieves theultrafiltrate from the blood stream. The ultrafiltrate will typicallyinclude a fraction of plasma water, electrolytes, peptides, proteins,target receptor molecules, target complex molecules, and targetmolecules. The sieved target molecules, target receptor molecules, andtarget complex molecules generally have a molecular size smaller thanthe nominal or effective pore size of the VLPH membrane (not expresslyshown).

[0032] Very large pore hemofilter 102 is preferably formed from one ormore biocompatible materials. In particular, very large pore hemofilter102 may include a membrane disposed within case 102 a. The membrane maybe formed from the group of biocompatible materials (e.g., polysulfone,polyacrylonitrile, polymethylmethacrylate, polyvinyl-alcohol, polyamide,polycarbonate, etc.) and biocompatible cellulose derivatives. The casemay be formed from polycarbonate or some other suitable biocompatiblematerial. The VLPH membrane will generally remove albumin from thepatient's blood. Depletion of albumin below acceptable levels will occurunless plasma colloid replacement fluid (described below) is provided inaccordance with teachings of the present invention.

[0033] Various types of membranes may be used. Examples of suchmembranes include either a parallel plate or hollow fiber format. Themembrane material may be any biocompatible material, typicallypolysulfone, polyacrylonitrile, polymethylmethacrylate,polyvinyl-alcohol, polyamide, polycarbonate, cellulose derivatives, andthe like. The effective molecular weight cutoff will allow for effectivesieving of target receptor molecules, target complex molecules, andtarget molecules, even after the membrane has undergone membranepolarization. The purpose of the membrane is to efficiently removetarget receptor molecules, target complex molecules, and targetmolecules, as well as associated plasma water and associated solutes.The size and other sieving characteristics of albumin or other targetreceptor molecules may change when bound with various target molecules.

[0034] For the embodiment represented by system 90, first tubing 101interfaces with patient 100 and blood pump 104. Blood pump 104 controlsthe flow of blood from patient 100. Blood exits from blood pump 104through second tubing 103 and flows to hemofilter 102. Hemofilter 102further interfaces with third tubing 105 and ultrafiltrate tubing 112.Filtered blood exiting hemofilter 102 through third tubing 105 flows tothree-way joint 125 and fourth tubing 107 where it returns to patient100.

[0035] Ultrafiltrate removed from the blood stream supplied by bloodpump 104 to hemofilter 102 may flow through ultrafiltrate tubing 112 tothree-way joint or three way valve 110 where the ultrafiltrate stream isdiscarded. Ultrafiltrate entering three-way joint 110 may be discardedthrough ultrafiltrate tubing 127, ultrafiltrate pump 106 b, and discardultrafiltrate tubing 121 to waste reservoir 119.

[0036] For some applications, ultrafiltrate recycling device 170 may becoupled with ultrafiltrate tubing 112 by tubing 172 and tubing 174.Ultrafiltrate recycling device 170 may include an adsorptive filter orother device operable to form clean ultrafiltrate by removing targetmolecules and target complex molecules from the ultrafiltrate. Controlvalve 176 may be disposed in ultrafiltrate tubing 112 between therespective junctions with tubing 172 and tubing 174. One or more controlvalves 178 and 180 may also be disposed in tubings 172 and 174 betweenultrafiltrate recycling device 170 and ultrafiltrate tubing 112. Forsome treatment therapies, control valve 176 may be opened and controlvalves 178 and/or 180 closed so that all of the ultrafiltrate streamwill flow from hemofilter 102 through tubing 112 to three-way joint 110to waste reservoir 119. For other treatment therapies, control valve 176may be closed and control valves 178 and 180 opened to direct theultrafiltrate stream from hemofilter 102 through ultrafiltrate recyclingdevice 170.

[0037] All or a selected portion of clean ultrafiltrate fromultrafiltrate recycling device 170 entering three-way joint 110 may bedirected to ultrafiltrate return pump 106 a and return ultrafiltratetubing 129. The clean ultrafiltrate may flow through three-way joint 125and tubing 107 to patient 100 along with the filtered blood stream. Allor selected portions of clean ultrafiltrate may be directed fromthree-way joint 110 to waste reservoir 119.

[0038] The rate of blood flowing through blood pump 104 and the totalamount of blood circulated through hemofilter 102 will depend on thecondition of patient 100, the molecular weight cutoff of the associatedhemofilter membrane, the body size of patient 100, and otherrequirements for effective treatment of the patient. The amount ofblood, the blood flow rate and the duration of treatment are preferablydetermined on a case by case basis after factoring the weight, the ageand the nature and severity of illness of patient 100. Often, blood flowrates may range from one hundred to two hundred milliliters/minute.Typically, total ultrafiltrate flow rate may range between one to nineliters per hour of which from zero to nine liters per hour may bediscarded. The discard rate will be determined by the fluid balancerequirements of patient 100 and the need for fluid removal. All cleanultrafiltrate not discarded may be returned to patient 100. The use ofreplacement fluid will be discussed later in more detail.

[0039] The composition of the material making up the blood pump,ultrafiltrate pumps, replacement fluid reservoir, tubing, ultrafiltratetubing and ultrafiltrate recycling device is preferably a biocompatiblematerial, such as polyvinylchloride, but not limited to this material.The tubing may be flexible and have dimensions complementary withassociated hemofilter connections, ultrafiltrate recycling deviceconnections, replacement fluid reservoir connection, joints, stop cocks,or pump heads.

[0040] Ultrafiltrate waste pump 106 b may be used to pump a portion orall of the ultrafiltrate to waste reservoir 119. Ultrafiltrate returnpump 106 a may be used to pump a portion or all of the recycled or cleanultrafiltrate back to patient 100. Ultrafiltrate return pump 106 a mayalso be used to infuse replacement fluid into patient 100. Tubing 107transfers filtered blood along with replacement fluid and/or recycledultrafiltrate or clean ultrafiltrate (if recycling is being done) topatient 100. Tubing 129 transfers recycled or clean ultrafiltrate andreplacement fluid from the ultrafiltrate return pump 106 a. The variouspumps are all optional so long as sufficient blood circuit pressure andflow are provided. Use of ultrafiltrate recycling device 170, andapportionment of ultrafiltrate to recycling and return to patient 100 orto waste reservoir 119 is operator dependent.

[0041] Examples of Very Large Pore Hemofiltration and Plasma ColloidExchange Therapy.

[0042] For use in IMRD, liver failure, exogenous intoxications and otherconditions associated with toxins in the blood, the present inventionteaches a very large pore hemofilter with a membrane capable of sievinga significant amount of target molecules, target receptor molecules, andtarget complex molecules over a significant portion of the therapy time.The very large pore hemofilter will typically have a sieving capacitysufficient to provide for an appropriately rapid exchange of targetcomplex molecules that are circulating in plasma, and removing targetmolecules located in tissues.

[0043] Now referring to FIG. 2, a flow diagram showing one method fordetermining hemofiltration treatment dosage according to teachings ofthe present invention is provided. The treatment method includesdetermining the medical condition of patient 100 at step 202 andmolecular weight cutoff for hemofilter 102 at step 204. In oneembodiment, a hemofilter may be used based on the nominal molecularweight cutoff, or another specific expression of the molecules that aresievable by the associated membrane. A hemofilter may also be selectedbased on membrane surface area and membrane material.

[0044] The method further includes determining patient 100's body size206. Determining body size may include measuring the body surface area,weight, mass, or lean body mass of patient 100. Alternatively, measuringbody size may include using other unambiguous, commonly used measure toaccount for patient 100's body size. The ultrafiltrate dosage is thencalculated using subject body size and the hemofilter molecular weightcutoff. In one embodiment the dosage will stipulate filter bloodflow/unit body size/unit time. Body size may be stated as surface area,body weight, body mass, lean body mass or any other unambiguous measure.Time may be measured in minutes, hours, or another suitable measure.

[0045] The dose of ultrafiltrate volume remove from patient 100 may beindexed to body size and time. Specifically, the volume of ultrafiltrateper unit of body size per unit time may be determined. Volume ofultrafiltrate may be stated in liters, milliliters, or another suitablevolume measure. Body size may be stated in kilograms, square meters ofbody surface area, kilograms of lean body mass or another suitablemeasure.

[0046] Blood is then withdrawn at step 210 from patient 100 according tothe expected rate of removal of ultrafiltrate from the blood stream andthe selected dosage of ultrafiltrate removal and pumped to hemofilter102 at step 212. Ultrafiltration of the blood using hemofilter 102occurs at step 214. Filtered blood is preferably returned to patient 100at step 216. Often treatment will be accomplished by continuous flow ofblood, filtered blood and ultrafiltrate. However, periodic orintermittent hemofiltration may also be conducted in accordance withteachings of the present invention depending upon the patient'scondition.

[0047] Fluid sieved from the blood by hemofilter 102 then enters anultrafiltrate stream at step 218. The ultrafiltrate stream removed byhemofilter 102 may be measured to ensure that the selected dosage ofultrafiltrate is removed. If the volume of the blood entering thehemofilter is not in accord with the selected dosage of ultrafiltrateremoval, the volume of blood removed and pumped to the hemofilter 102may be selectively increased or decreased to produce the selected dosageof ultrafiltrate removal. All or a selected portion of the ultrafiltratemay be directed into the waste stream at step 220, where it isultimately discarded at step 222.

[0048] Optional step 270 may also be included to recycle or clean theultrafiltrate. Replacement fluid may be added at step 272 to the cleanedor recycled ultrafiltrate. The clean ultrafiltrate may be returned tothe ultrafiltrate stream at step 224 or may be discarded at step 220.

[0049] The result of dose quantification and selection will be to assureequally intense hemofiltration-ultrafiltration treatment is provided toeach subject receiving any given dose, regardless of body size. Dosewill allow comparison of therapeutic regimens, duration, and hemofilterswith respect to effectiveness, side effects, and costs.

[0050] Removal or exchange of target molecules, target receptormolecules, and target complex molecules depends on a number ofvariables. These variables include duration of therapy, membrane sievingcoefficients for target molecules, target receptor molecules, and targetcomplex molecules, and filter blood and ultrafiltrate flow rates, amongothers. Short duration (but intense) therapy can rapidly remove targetmolecules, target receptor molecules, and target complex molecules fromplasma, but may leave insufficient time for target molecules, targetreceptor molecules, and target complex molecules to move from tissuesites into plasma, thus limiting the total body reduction of targetmolecules. Longer treatment times will allow for movement of targetmolecules from tissues, but, if sieving coefficient is excessively high,then plasma colloid replacement fluid would not be efficiently used.Filter blood and ultrafiltrate flow will also materially affectefficiency of treatment. Appropriate treatment duration will depend onthe nature of the pathophysiologic condition to be treated, itsseverity, and other relevant clinical factors as assessed by aphysician. Thus, the combinations of treatment duration, sievingcoefficient, and filter blood and ultrafiltrate flow will vary.

[0051] A sieving coefficient approaching (or even exceeding) 1.0 fortarget complex molecules (or other target molecules) may often providethe most efficient removal of target molecules, and in certaincircumstances will be most desirable. Sieving coefficients for targetcomplex molecules (and target molecules) above 0.5 will also bereasonably effective. Lower sieving coefficients (between about 0.05 and0.5) may provide sufficiently effective sieving under certain treatmentcircumstances. Sieving coefficients that are too low either initially orafter membrane polarization are considered inadequate for VLPH.

[0052] The sieving characteristics of membrane pores depends not only onthe nominal pore size, but also on the physical, chemical, andelectrical characteristics of the material from which it is made and theparticular manufacturing technique used to produce the membrane. As aresult, the sieving coefficient for albumin and other target receptormolecules, and target molecules, may vary among membranes with the samenominal pore size. However, the nominal molecular weight cutoff toprovide adequate sieving of target receptor molecules, target complexmolecules, and target molecules, is expected to be approximately 150,000to 500,000 Dalton. Very large pore hemofilter 102 will typically havepores with a molecular weight cutoff substantially less than that ofplasmapheresis filters, so that no significant amount of immunoglobulinsand similar large molecules will be sieved from the blood.

[0053] A 150-500 kD very large pore hemofilter may be used to accomplishplasma colloid exchange therapy (PCET) in accordance with teachings ofthe present invention. The very large pore hemofilter may filter patientblood with post filter blood returning to patient 100 and ultrafiltratecontaining plasma water, target complex molecules, target receptormolecules, and target molecules, discarded to waste reservoir 119 atstep 222. Alternatively, all or portions of the ultrafiltrate may becleaned and recycled back to patient 100 at steps 270, 224 and 226.Sieving albumin and other target complex molecules, should have theintended effect of rapidly reducing target molecules, but will alsorapidly deplete plasma albumin and other target receptor molecules.Therefore, an infusion into the patient of plasma colloid replacementfluid (see below) will be administered in sufficient quantity toaccomplish two goals. First, to maintain a serum albumin sufficient topreserve adequate plasma oncotic pressure. Second, to provide freshalbumin and/or other target receptor molecules, with binding sitesunoccupied by IM and/or toxins, which can attract target molecules fromtissue spaces and tissue binding sites, and subsequently clear targetmolecules through the very large pore hemofilter.

[0054] The continuous exchange of fresh albumin and other targetreceptor molecules, with its broad distribution through the circulation,should allow intravascular binding kinetics favorable to the removal oftarget molecules from tissue sites. The dwell time of fresh albuminand/or other target receptor molecules in the body should allowsaturation of the target receptor molecules, and make for efficient useof target receptor molecules. In this manner, removal of targetmolecules from blood and tissue can be accomplished in IMRD, liverfailure, exogenous intoxication, and other conditions associated withtoxins in the blood.

[0055] As with all hemofiltration procedures, a replacement fluid willbe needed. Current replacement fluids are often crystalloid only,consisting of pharmaceutical grade, balanced salt solutions. The presentinvention teaches a plasma colloid replacement fluid (“PCRF”) whichincludes pharmaceutical grade balanced salt solution containing albuminand/or other target receptor molecules and/or other physiologicmolecules in a sufficient concentration to adequately replenish ongoinglosses. For example, the concentration of albumin could range from 0.5gm/100 ml to 10.0 gm/100 ml and would be operator determined. Theconcentration of other target receptor molecules would be operatordetermined. Whether to include specific target receptor molecules, theselection and amounts of target receptor molecules, are operatordependent.

[0056] PCRF will be used as all or part of the replacement fluid in theplasma colloid exchange therapy. PCRF may be added to the bloodcirculation at any point, but preferably in the post dilution mode inthe very large pore hemofilter circuit. For example see step 250 in FIG.2. The plasma colloid exchange therapy may be used in a single passmode, with discard of filtrate, and infusion of PCRF. Alternatively,plasma colloid exchange therapy may be done in a filtrate recycling mode(See step 272) with recycling of filtrate through a recycling system sothat all or part of the ultrafiltrate may be returned to the mammal.PCRF may also be infused during the recycling.

[0057] For the embodiment of the present invention as shown in FIG. 1,system 90 includes replacement fluid source 150. Plasma colloidreplacement fluid may be supplied by replacement fluid source 150. Forthe embodiment shown in FIG. 1, replacement fluid source 150 includesfluid reservoir 152, tubing 154 and control valve 156. Various types ofintravenous bags or other containers may be used as reservoir 152.

[0058] For this particular embodiment, tubing 154 is coupled with tubing129 between ultrafiltrate pump 106 a and three-way joint 110. Reservoir152 preferably includes at least one port which may be coupled withtubing 154 to supply PCRF from reservoir 152 to tubing 129. Controlvalve 156 may be used to regulate the flow rate of PCRF in accordancewith teachings of the present invention. Additional PCRF may also beadded to reservoir 152 using this same port or another port (notexpressly shown).

[0059] For some applications replacement fluid source 150 may begenerally described as a replacement fluid kit. Multiple replacementfluid kits may be maintained in the vicinity of hemofilter 102. Forexample, each replacement fluid kit may include a respective reservoir152 filled with different types of PCRF. An appropriate connector (notexpressly shown) may also be provided to allow quickly engaging anddisengaging reservoir 152 with tubing 154. For other applications,tubing 154 may be provided as part of each replacement fluid kit. Anappropriate connection (not expressly shown) may be provided to coupletubing 154 with tubing 129 or with other portions of the extra corporealblood circuit associated with hemofilter 102.

[0060] Although the present invention has been described with respect toa specific preferred embodiment thereof, various changes andmodifications may be suggested to one skilled in the art and it isintended that the present invention encompass such changes andmodifications fall within the scope of the appended claims.

What is claimed is:
 1. A fluid for replacing target receptor moleculescontaminated with at least one inflammatory mediator removed from apatient's blood during hemofiltration comprising a pharmaceutical gradesolution having corresponding clean target receptor molecules which arenot contaminated.
 2. The fluid of claim 1 wherein the hemofiltrationcomprises using a very large pore hemofilter.
 3. The fluid of claim 1further comprising a concentration of albumin in the fluid greater thanapproximately 0.5 grams per one hundred milliliters.
 4. The fluid ofclaim 1 further comprising a concentration of albumin in the fluid lessthan approximately twenty grams per one hundred milliliters.
 5. Thefluid of claim 1 further comprising a plurality of clean target receptormolecules corresponding with a plurality of target receptor moleculescontaminated with more than one inflammatory mediator removed from thepatient's blood.
 6. A fluid for replacing target receptor moleculescontaminated with at least one toxin removed from a patient's bloodduring hemofiltration comprising a pharmaceutical grade solution havingcorresponding clean target receptor molecules which are notcontaminated.
 7. The fluid of claim 6 wherein the hemofiltrationcomprises using a very large pore hemofilter.
 8. The fluid of claim 6further comprising a concentration of albumin in the fluid greater thanapproximately 0.5 grams per one hundred milliliters.
 9. The fluid ofclaim 6 further comprising a concentration of albumin in the fluid lessthan approximately twenty grams per one hundred milliliters.
 10. Thefluid of claim 6 further comprising a plurality of clean target receptormolecules corresponding with a plurality of target receptor moleculescontaminated with more than one toxin removed from the patient's blood.11. A replacement fluid kit for attachment to an extracorporeal bloodcircuit during hemofiltration, the kit comprising: a replacement fluidand a reservoir for the replacement fluid; the reservoir having at leastone port operable to communicate replacement fluid from the reservoir; acoupling operable to allow flow of the replacement fluid from the portto the extracorporeal blood circuit; and the replacement fluid formed inpart by a pharmaceutical grade liquid, suitable for infusion into apatient's blood circulatory system, with a concentration of albumin atleast sufficient to maintain a prescribed albumin concentration in thepatient's blood circulatory system.
 12. An extracorporeal blood circuitfor the filtration of a patient's blood comprising: a circuit operableto remove and to return a portion of a patient's blood supply; a bloodfilter operably coupled with the circuit to allow the portion of thepatient's blood to flow therethrough; the blood filter having aneffective molecular cutoff sufficiently large to sieve more than anominal amount of target complex molecules from the portion of thepatient's blood; the effective molecular weight cutoff less thanapproximately five million Daltons; and a source for infusingcorresponding clean target receptor molecules into the blood circuit.13. The extracorporeal blood circuit of claim 12, further comprising theeffective molecular weight cutoff less than approximately one millionDaltons.
 14. The extracorporeal blood circuit of claim 12, furthercomprising the effective molecular weight cutoff less than approximatelyfive hundred thousand Daltons.
 15. A blood filter comprising a membranehaving an effective molecular weight cutoff sufficiently large to sievemore than a nominal amount of target complex molecules duringhemofiltration and the effective molecular weight cutoff less thanapproximately one million Daltons.
 16. The blood filter of claim 15further comprising a hemofilter operable to sieve target complexmolecules from a patient's blood to form a filtered blood stream and anultrafiltrate stream containing target complex molecules.
 17. A methodfor removing target molecules and target complex molecules from apatient's blood, comprising: circulating a stream of the patient's bloodthrough a very large pore hemofilter having a nominal molecular weightcutoff greater than approximately 150,000 Daltons to sieve targetmolecules and target complex molecules from the blood stream and thenominal molecular weight cutoff less than approximately 1,000,000Daltons to avoid removal of significant amounts of immunoglobulins andsimilar large molecules to prevent increasing the risk of opportunisticinfection; removing an ultrafiltrate containing the target molecules andtarget complex molecules from the blood stream using the hemofilter;replacing the ultrafiltrate removed from the blood stream with areplacement fluid having clean target receptor molecules; providingsufficient clean albumin to maintain adequate plasma oncotic pressure;and providing the clean albumin and clean target receptor molecules toattract additional inflammatory mediators and toxins from tissue spacesand tissue binding sites in a patient.
 18. The method of claim 17further comprising infusion of the replacement fluid directly into thepatient.
 19. The method of claim 17 further comprising infusion of thereplacement fluid into a blood flow circuit associated with thehemofilter.
 20. The method of claim 17 further comprising infusion ofthe replacement fluid directly into the patient and into a blood flowcircuit associated with the hemofilter.